When Heme Attacks: After Trauma, The Molecule that Makes
Life Possible Rampages

PENN Researchers Find How Heme Harms - And How To Prevent The Damage

(Philadelphia, PA) - Heme, the iron-bearing, oxygen-carrying
core of hemoglobin, makes it possible for blood to carry oxygen, but researchers
from the University of Pennsylvania School of Medicine have determined
how free-floating heme can also make traumatic events worse by damaging tissue.
The Penn researchers present their findings in the October 2nd issue of the
journal Nature. Fortunately, the researchers also identified a chemical
that can be targeted by drug developers to impede the deleterious effects of
free-floating heme.

Following a traumatic event - such as an accident, a stroke, a heart attack
or even surgery - heme floods the spaces between and inside cells and exacerbates
the damage. It does so by shutting down an important cell membrane channel,
an action that kills neurons and constricts blood vessels. While investigating
this process, the researchers also determined that a chemical called NS1619
restores the function of the cell membrane channel. NS1619 and its derivatives
could be the source for a new drug - one that prevents the secondary events
that worsen trauma damage.

"Following a heart attack, a stroke, or any really severe physical injury,
heme is literally shaken loose from hemoglobin," said Xiang Dong Tang, MD,
PhD, Staff Scientist in Penn's Department of Physiology. "Normally, cells
can compensate and recycle loose heme. But when larger concentrations are released,
heme can gum up the works, specifically the Maxi-K ion channel, a cell membrane
protein important for blood vessel relaxation and neuron excitability."

Maxi-K is a channel that moves potassium ions out of cells. In the Nature
paper, Tang and his colleagues prove that the Maxi-K protein possesses sites
that bind heme. If these sites were removed or altered, heme could not effect
Maxi-K proteins. "Maxi-K is found in the lining of blood vessels. When it is
turned off, the vessel constricts, increasing blood pressure, which is decidedly
not beneficial following a heart attack, " said Toshinori Hoshi, PhD,
Associate Professor in Penn's Department of Physiology and co-author of the
Nature article. "In neurons, disrupting Maxi-K leads to excessive calcium
accumulation. Eventually, this ionic buildup triggers cell suicide and, therefore,
the loss of the neuron."

The chemical heme is essential for most forms of life. It exists in hemoglobin
for oxygen transport, in cytochromes for cellular energy production, and in
guanylate cyclase for blood pressure regulation. The molecule itself is tiny,
a flat snowflake of a carbon framework surrounding a single atom of iron, but
it is crucial for the cellular process of respiration and the action of nirtroglycerine.

"Generally, the heme molecule is attached to larger molecules, such as hemoglobin,
but it is easily set loose. Indeed, there is an entire cellular industry behind
recycling and reusing 'lost' heme," said Tang. "But that system can get overwhelmed
in times of serious trauma and bleeding."

Studying the heme recycling system might prove useful in developing treatments
for preventing the secondary damage set off by heme. Certain cells, such as
neurons, do have ways of transporting heme. If the 'heme transport' is identified
and the specific blocker is found, it could help prevent symptoms resulting
from trauma and bleeding.

Meanwhile, according to Tang and his colleagues, there is already a known agent
that can relieve Maxi-K from heme inhibition. NS1619 is known as the "Maxi-K
opener," and, as the researchers have shown, readily reverses the heme-mediated
inhibition.

"I can envision the use of a drug similar to NS1619 as an emergency treatment,"
said Tang. "In the emergency room, after an accident or heart attack, it could
be used to keep the damage from continuing on a cellular level - before it could
result in bad effects for the entire body."

Scientists also contributing to this research include Rong Xu from Penn, Mark
F. Reynolds, from St. Joseph's University, Marcia L. Garcia, from Merck Research
Laboratories, and Stefan H. Heinemann, from Friedrich Schiller University.

Funding for this research came from the National Institutes of Health.

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PENN Medicine is a $2.2 billion enterprise dedicated
to the related missions of medical education, biomedical research, and high-quality
patient care. PENN Medicine consists of the University of Pennsylvania School
of Medicine (founded in 1765 as the nation's first medical school) and the University
of Pennsylvania Health System (created in 1993 as the nation's first integrated
academic health system).

Penn's School of Medicine is ranked #2 in the
nation for receipt of NIH research funds; and ranked #4 in the nation in U.S.
News & World Report's most recent ranking of top research-oriented medical schools.
Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is
recognized worldwide for its superior education and training of the next generation
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Penn Health System consists of four hospitals (including its
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